The long-term goal is to understand the control of contractility, stretch resistance and relaxation in smooth muscle by neurotransmitters, hormones, ions and pharmacological agents. The smooth muscle of pulmonary arteries displays physiological and pharmacological responses which are different from those of systemic arteries. In response to chronic alveolar hypoxia and certain toxins, the media of the small pulmonary arteries in certain species, including man, undergoes hypertrophy/hyperplasia, a "remodeling" which contributes to pulmonary vascular resistance and leads to pulmonary hypertension. Experiments recently completed in our laboratory have demonstrated differences in membrane properties of smooth muscle cells in normal main and small pulmonary arteries and clearly indicate that membrane properties in each of these (conducting and resistance vessels, respectively) are characteristically altered during medial hypertrophy/hyperplasia in chronic hypoxic rats. Details of the catecholaminergic, cholinergic and peptidergic innervation have also been studied in rat models of pulmonary hypertension. In the proposed studies, membrane properties, contractility and innervation of smooth muscle fibers in the main and small pulmonary arteries of rats and guinea pigs will be analyzed by electrophysiological, pharmacological, histochemical and ultrastructural methods. Mechanical responses to pharmacological agents in main pulmonary artery and in resistance vessels of less than 250 microns in diameter are to be recorded simultaneously with membrane potentials. Excitation-contraction coupling will be studied in chemically "skinned" fibers in vessel segments. This project, in conjunction with a collaborative study on other animal models of pulmonary hypertension, can provide insights into involvement of smooth muscles in clinical states of pulmonary (and systemic) hypertension and, in particular, into mechanisms of changes in responsiveness associated with hypertension.